Retargeted adenoviruses for local IgA and CD47 blocker production as a novel cancer therapy.

Despite advances in IgG-based cancer immunotherapy, challenges remain in effectively engaging innate immune responses against solid tumors. Here, IgA antibodies hold promise due to their ability to activate neutrophils and macrophages. We present a novel retargeted adenovirus-mediated approach that transforms cancer cells into "biofactories" for localized production of monomeric or dimeric IgA antibodies and a CD47 blocker to potentiate the effect of IgA antibodies. With our approach, tumor cells effectively produced IgA antibodies against tumor antigens such as EGFR or EpCAM and a soluble SIRPα-Fc fusion protein, which blocks the CD47-SIRPα axis. In a perfused tumor-on-a-chip model, locally produced IgA triggered neutrophil- and macrophage-mediated tumor cell killing, further potentiated by SIRPα-Fc co-production. In FcαRI-transgenic, tumor-bearing mice, intratumoral adenoviral injection induced strong local IgA and SIRPα-Fc expression, immune cell infiltration, and more than 50% tumor volume reduction after a single treatment. We found that dimeric IgA exerts stronger effects than monomeric IgA. Together, these results demonstrate that adenovirus-mediated, tumor-restricted delivery of IgA antibodies and CD47 blockade effectively engages innate immune mechanisms and has therapeutic promise.